Pain caused by a primary lesion or dysfunction in the nervous system is defined as neuropathic pain, with nerve trauma, diabetes, multiple sclerosis, HIV infection, and various forms of malignancies being some of the common causes. Approximately 3.75 million cases of chronic neuropathic pain are reported in the United States alone. R. N. Harden, “Chronic Neuropathic Pain: Mechanisms, Diagnosis, and Treatment”, The Neurologist, 11: 111 (2005). In addition to patient morbidity, management of chronic neuropathic pain exerts significant burden on health care spending.
Despite the availability of several drugs including opioids, NSAID's and tricyclics, a significant number of patients have unsatisfactory pain control, and may experience undesirable side effects. Enhanced neuronal activity, a prominent feature of neuropathic pain, has been consistently reported in various animal nerve injury models of chronic pain. See, e.g., Coggeshall, et al., “A-fiber sensory input induces neuronal cell death in the dorsal horn of the adult rat spinal cord”, J. Comp. Neurol., 435: 276-282 (2001); Govrin-Lippmann, et al., “Ongoing activity in severed nerves: source and variation with time”, Brain Res., 159 406-410 (1978); Wu, et al., “Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers”, Journal of Neuroscience, 21: RC140 (2001).
It has been argued that excitatory neurotransmitters, such as glutamate, released in response to injury-induced aberrant neuronal impulses, leads to calcium mediated excitotoxicity and subsequent cellular injury at the level of the dorsal root ganglion (DRG) and spinal cord. See, e.g., D. W. Choi, “Calcium and Excitotoxic Neuronal Injury”, Ann. N.Y. Acad. Sci., 747: 162-171 (2006); Coggeshall, et al., “A-fiber sensory input induces neuronal cell death in the dorsal horn of the adult rat spinal cord”, J. Comp. Neurol., 435: 276-282 (2001); C. J. Woolf, “Neuronal Plasticity: Increasing the Gain in Pain”, Science, 288:1765-1768 (2000).
However, attempts to block injury-induced neuronal discharges using short-term nerve conduction blockers such as lidocaine and bupivacaine microspheres have been largely unsuccessful. Wen, et al., “Nerve Conduction Blockade in the Sciatic Nerve Prevents but Does Not Reverse the Activation of p38 Mitogen-activated Protein Kinase in Spinal Microglia in the Rat Spared Nerve Injury Model”, Anesthesiology, 107: 312-321 (2007); Suter, et al., “Development of neuropathic pain in the rat spared nerve injury model is not prevented by a peripheral nerve block”, Anesthesiology, 99(6):1402-8 (2003). In fact, amino-amide local anesthetics themselves, such as bupivacaine and lidocaine, are known to cause neurotoxicity. Gold, et al., “Lidocaine toxicity in primary afferent neurons from the rat”, J. Pharmacol. Exp. Ther., 285(2):413-21 (1998); Radwan, et al., “The neurotoxicity of local anesthetics on growing neurons: a comparative study of lidocaine, bupivacaine, mepivacaine, and ropivacaine”, Anesth. Analg., 94:319-24 (2002). Long-term nerve blockade and its effect on the onset and maintenance of neuropathic pain are yet to be determined.
The development of local anesthetics to provide prolonged analgesia from a single injection has encountered three principal challenges: (1) inadequate duration of action; (2) systemic toxicity; and (3) adverse local tissue reaction.
A wide variety of controlled-release technologies have been employed to extend the duration of nerve block, but most such systems result at best in a several-fold extension of duration compared to unencapsulated drugs. Approaches that encapsulate synergistic drug combinations have achieved nerve blocks lasting many days. For example, co-encapsulation of bupivacaine and dexamethasone in polymeric microspheres produced nerve blocks lasting more than four days. Drager, et al., Anesthesiology, 89(4):969-979 (1998). Co-encapsulation of site 1 sodium channel blockers (which block the sodium channel at site 1 on the outer surface) with conventional local anesthetics also greatly prolonged sciatic nerve blockade. Addition of dexamethasone prolonged the sciatic nerve blockade to more than nine days in the rat (Kohane, et al, Pain, 104(1-2):415-421 (2003)).
However, tissue reaction to such formulations has been problematic. Conventional local anesthetics are intrinsically myotoxic (Padera, et al., Anesthesiology, 108(5):921-928 (2008); Pere, et al., Reg Anesth, 18(5):304-307 (1993)). They are also myotoxic when released from a wide range of delivery systems (Padera, et al., Anesthesiology, 108(5):921-928 (2008); Jia, et al., Biomaterials, 25(19):4797-4804 (2004)), even when the delivery systems themselves are minimally toxic. The myotoxicity of bupivacaine increases dramatically over extended durations of exposure (Padera, et al., Anesthesiology, 108(5):921-928 (2008)), suggesting that myotoxicity may be an inevitable consequence of sustained release of such compounds.
Conventional local anesthetics are also neurotoxic (Zimmer, et al., Anaesthesist, 56(5):449-453 (2007); Yamashita, et al., Anesth Analg, 97(2):512-519 (2003)). The presence of particles themselves enhances local anesthetic myotoxicity in vivo (Padera, et al., Anesthesiology, 108(5):921-928 (2008), and can cause inflammatory responses at the nerve that may considerably outlast the duration of blockade (Kohane, et al, Pain, 104(1-2):415-421 (2003); Padera, et al., Anesthesiology, 108(5):921-928 (2008); and Kohane, et al., J Biomed Mater Res., 59(3):450-459 (2002)).
U.S. Pat. No. 6,326,020 to Kohane, et al. discloses compositions containing a combination of naturally occurring site 1 sodium channel blockers, with other agents such as local anesthetics, vasoconstrictors, glutocorticoids, or adrenergic drugs for prolonged duration of nerve block. Site 1 sodium channel blockers do not cause myo- or neurotoxicity (Barnet, et al., Pain 110(1-2):432-438 (2004); Sakura, et al., Anesth Analg, 81(2):338-346 (1995)), which makes them desirable for an extended release formulation. U.S. Pat. No. 6,326,020 discloses poly(lactic acid-glycolic acid) microspheres containing TTX (at 0.1% theoretical loading) alone, in a carrier fluid containing epinephrine, which produces nerve block lasting about six hours with an onset of more than one hour. TTX without epinephrine has been shown to produce sciatic nerve block, but with considerable toxicity at the most effective doses (Kohane, et al., Anesthesiology, 89(1):119-131 (1998). Studies by Kohane, et al, Pain, 104(1-2):415-421 (2003) employing polymeric microspheres of TTX alone showed that TTX was lethal (at 0.1% w/w) or ineffective for nerve block (at 0.05% w/w), producing a median block of 0 min.
Additionally, it is extremely difficult to encapsulate effectively these extremely potent local anesthetics in polymeric particles since they are hydrophilic and the systemic toxicity from their initial rapid release is dose-limiting (Barnet, et al., Anesth Analg, 101(6):1838-1843 (2005); Kohane, et al., Anesthesiology, 89(1):119-131 (1998)). This makes the development of particulate systems based entirely on such compounds (i.e. without inclusion of conventional local anesthetics) very difficult.
There is a need for a formulation and/or method for preventing or delaying the onset of neuropathic pain, such as hyperalgesia or allodynia.
It is an object of the present invention to provide a formulation for preventing or delaying the onset of neuropathic pain, such as hyperalgesia or allodynia.
It is still another object of the present invention to provide a method for preventing or delaying the onset of neuropathic pain, such as hyperalgesia or allodynia.